CD40 antigen is a cell surface transmembrane 45-kDa glycoprotein receptor expressed on a number of cell types, including B-lymphocytes (“B cells”). Stamenkovic et al. (1989) EMBO J. 8:1403-1410. It is a member of the tumor necrosis factor receptor family and, like other members, it appears to possess no intrinsic signaling capacity (e.g., kinase activity), suggesting that signal transduction is likely mediated by associating molecules. CD40 antigen has a short cytoplasmic tail (65 amino acid residues), and mutagenesis studies suggest that Thr234 in the cytoplasmic domain is essential for signal transduction. Inui et al. (1990) Eur. J. Immunol. 20:1747-1753.
The ligand to CD40, “CD40L”, is expressed on activated T-helper cells. Armitage et al. (1992) Nature 357:80-82. Activation of CD40 receptor is critical for B-cell proliferation, cytokine production, immunoglobulin class switching, and rescue of germinal center B cells from apoptosis following somatic mutation. Banchereau et al. (1991) Science 251:70-72; Liu et al. (1989) Nature 342:929-931; and Zhang et al. (1991) J. Immunol. 146:1836-1842.
Mutations in CD40L result in an immuno-deficiency (X-linked hyper-IgM syndrome) characterized by IgM-producing B cells that do not form germinal centers in response to foreign antigens. Allen et al. (1993) Science 259:990-993; Korthauer (1993) Nature 361:539-541; and Fuleihan (1993) Proc. Natl. Acad. Sci. U.S.A. 90:2170-2173. Hyper-IgM syndrome is a rare disorder characterized by recurrent infections and is associated with low serum levels of IgG, IgA, and IgE, and normal or increased levels of IgM. Clinical features of this syndrome include recurrent bacterial infections of the upper and lower respiratory tract, usually beginning in the first or second year of life. Ochs et al. (1993) Curr. Opin. Pediatr. 5:684-691. Pneumocystis carinii pneumonia in early infancy, neutropenia, thrombocytopenia, hemolytic anemia, nephritis and arthritis also have been associated with this genetic disorder.
Activation and transduction through the CD40 pathway is in large part, responsible for B cell activation and accordingly, the cellular immune response. However, it is still unknown how the receptor transduces its signal. Thus, in view of the variety of immune responses mediated through the CD40 receptor, it would be desirable to have a means to study the CD40 receptor pathway as well as modulate its effects. This invention satisfies this need and provides related advantages as well.